Prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP) affects reproductive outcomes in female mice

Niermann, Sarah; Rattan, Saniya; Brehm, Emily; Flaws, Jodi A.

doi:10.1016/j.reprotox.2015.02.013

Cited by 74 publications

(59 citation statements)

References 44 publications

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“…For example, early rodent studies found that DEHP exposure was associated with decreased fetal and birth weight (31, 32]), while similar recent studies are consistent with our findings of no association (33, 34). Animal studies of in utero DBP exposure have also observed inconsistent effects on birth weight, with several studies reporting no effect (35-38), while others reported either decreased (39-41) or increased (42) birth weight.…”

Section: Discussionsupporting

confidence: 92%

Maternal phthalate exposure during early pregnancy and at delivery in relation to gestational age and size at birth: A preliminary analysis

Watkins

Milewski

Domino

et al. 2016

Reproductive Toxicology

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Epidemiologic studies of in utero phthalate exposure and birth outcomes have had conflicting findings. The objective of this study was to characterize maternal phthalate exposure across pregnancy, examine associations between maternal phthalate levels and infant size and gestational age at birth, and investigate relationships between concurrent bisphenol A (BPA) and phthalate exposure and birth outcomes. Women in the Michigan Mother-Infant Pairs cohort provided urine and blood samples during their first trimester and at delivery. Urinary phthalate metabolites and serum BPA were measured at both time points, and birth weight, length, head circumference, and gestational age were recorded from medical records. Maternal DEHP metabolite concentrations were significantly higher at delivery compared to the first trimester (p<0.05), suggesting increased DEHP exposure late in pregnancy. A number of phthalate metabolites were associated with birth size and gestational age in patterns that varied by sex and timing of exposure, independent of BPA exposure.

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Section: Discussionsupporting

confidence: 92%

Maternal phthalate exposure during early pregnancy and at delivery in relation to gestational age and size at birth: A preliminary analysis

Watkins

Milewski

Domino

et al. 2016

Reproductive Toxicology

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“…Reproductive outcome of F0 dams treated with DEHP from gestational day 1 to 19. Previous studies have reported that DEHP is able to induce a dose-dependent decrease in mouse fertility (23), and affect reproductive outcomes in female mice (24). In the present study, no significant decline in fertility was exhibited by F0 dams treated with 0.05 mg/kg DEHP; however, the abortion rate was 100% in the 500 mg/kg DEHP dose group compared with 0% in the control and 0.05 mg/kg DEHP groups.…”

Section: Discussioncontrasting

confidence: 63%

In utero exposure to di-(2-ethylhexyl) phthalate induces metabolic disorder and increases fat accumulation in visceral depots of C57BL/6J mice offspring

Liu

Wang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract.Excessive visceral fat accumulation is associated with metabolic disorders. Di-(2-ethylhexyl) phthalate (DEHP), a candidate environmental obesogen, affects lipid metabolism and adipogenesis. Perinatal exposure to DEHP may be associated with metabolic disorders of dams and offspring. The aim of the present study was to explore the effects of exposure of pregnant dams to DEHP on the metabolism and fat distribution of their offspring, and to determine the mechanisms for these effects. Pregnant C57BL/6J mice were administered DEHP via gavage (0.05 or 500 mg/kg/day) from gestational days 1-19. Pups were sacrificed at nine weeks of age. Serum leptin, insulin, lipid and fasting glucose levels, and the weights of the inguinal (subcutaneous) and gonadal (visceral) fat pads were determined. mRNA expression levels of two developmental genes, T-box 15 (Tbx15) and glypican 4 (Gpc4) were detected in fat tissues. A 100% abortion rate was exhibited in 500 mg/kg DEHP-treated dams, whereas exposure to 0.05 mg/kg DEHP did not affect reproductive outcomes. Pups from the 0.05 mg/kg exposure group were used for subsequent experimentation. Serum leptin, insulin, lipid and fasting glucose concentrations in these pups were significantly higher than those of control pups (P<0.05). Although no significant change in body weight was detected, the visceral fat weights of DEHP-exposed pups were significantly higher than those of control pups (P<0.05). Compared with controls, mRNA expression levels of Tbx15 in subcutaneous fat and Gpc4 in visceral fat were significantly increased among DEHP-exposed pups (P<0.01). The present results suggest that in utero exposure to an environmentally safe dose of DEHP may lead to excessive visceral fat accumulation and metabolic disorders in offspring and that aberrant expression of Tbx15 and Gpc4 may have an important role in these effects.

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“…This is the first time this phthalate mixture has been tested in vivo . Thus, doses of phthalate mixture were chosen to cover a wide environmentally relevant range and to include some of the doses of individual phthalates that have been shown to adversely affect reproductive health during prenatal exposure [17–19, 23]. The estimated general population daily exposure level of DEHP is 3–30 μg/kg/day [24].…”

Section: Methodsmentioning

confidence: 99%

“…We also included two high doses of mixture (200 and 500 mg/kg/day, which contain approximately 40 and 100 mg/kg/day of DEHP, respectively) to test the effects of this mixture at a level higher than human expose range and to compare our results with available information from single phthalate studies that used doses close to this level. Previous studies have shown that gestational exposure to DEHP decreased the thickness of thecal cell layers at 50 and 300 mg/kg/day [23], disrupted steroidogenic enzyme gene expression and increased estradiol levels at 100 mg/kg/day [19], increased preantral follicle numbers at 200 μg/kg/day and 500 mg/kg/day [17], increased ovarian weights at 0.05 and 5 mg/kg/day [18], and induced breeding complications at 200 μg/kg/day and 750 mg/kg/day [17]. …”

Section: Methodsmentioning

confidence: 99%

“…However, the effects of prenatal phthalate exposure on female reproduction in the offspring are less extensively studied. Published studies have shown that gestational exposure to DEHP affects folliculogenesis [17], reduces oocyte quality [18], decreases steroidogenic capacity [18, 19], delays puberty [19], and decreases fertility [17, 18]. …”

Section: Introductionmentioning

confidence: 99%

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Prenatal exposure to an environmentally relevant phthalate mixture disrupts reproduction in F1 female mice

Zhou

Gao

Flaws

2017

Toxicology and Applied Pharmacology

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Phthalates are used in a large variety of products, such as building materials, medical devices, and personal care products. Most previous studies on the toxicity of phthalates have focused on single phthalates, but it is also important to study the effects of phthalate mixtures because humans are exposed to phthalate mixtures. Thus, we tested the hypothesis that prenatal exposure to an environmentally relevant phthalate mixture adversely affects female reproduction in mice. To test this hypothesis, pregnant CD-1 dams were orally dosed with vehicle (tocopherol-stripped corn oil) or a phthalate mixture (20 and 200 μg/kg/day, 200 and 500 mg/kg/day) daily from gestational day 10 to birth. The mixture was based on the composition of phthalates detected in urine samples from pregnant women in Illinois. The mixture included 35% diethyl phthalate, 21% di(2-ethylhexyl) phthalate, 15% dibutyl phthalate, 15% diisononyl phthalate, 8% diisobutyl phthalate, and 5% benzylbutyl phthalate. Female mice born to the exposed dams were subjected to tissue collections and fertility tests at different ages. Our results indicate that prenatal exposure to the phthalate mixture significantly increased uterine weight and decreased anogenital distance on postnatal days 8 and 60, induced cystic ovaries at 13 months, disrupted estrous cyclicity, reduced fertility-related indices, and caused some breeding complications at 3, 6, and 9 months of age. Collectively, our data suggest that prenatal exposure to an environmentally relevant phthalate mixture disrupts aspects of female reproduction in mice.

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Prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP) affects reproductive outcomes in female mice

Cited by 74 publications

References 44 publications

Maternal phthalate exposure during early pregnancy and at delivery in relation to gestational age and size at birth: A preliminary analysis

Maternal phthalate exposure during early pregnancy and at delivery in relation to gestational age and size at birth: A preliminary analysis

In utero exposure to di-(2-ethylhexyl) phthalate induces metabolic disorder and increases fat accumulation in visceral depots of C57BL/6J mice offspring

Prenatal exposure to an environmentally relevant phthalate mixture disrupts reproduction in F1 female mice

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